Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

Area of Science:

• Immunology
• Inflammation Biology
• Molecular Medicine

Background:

• Sarcoidosis is a multisystemic inflammatory disease characterized by granuloma formation.
• Pentaxin 3 (PTX3) is involved in innate immunity and inflammation resolution, but its role in granuloma formation is unclear.

Purpose of the Study:

• To investigate the role of PTX3 in modulating pathogenic signals driving granuloma formation and inflammation in sarcoidosis.
• To evaluate PTX3 as a potential therapeutic target for sarcoidosis.

Main Methods:

• Utilized peripheral blood mononuclear cells from sarcoidosis patients with PTX3 variants and PTX3-deficient mice.
• Assessed PTX3's role in experimental in vitro and in vivo granuloma formation models.
• Analyzed mechanisms in tissue and bronchoalveolar lavage (BAL) samples, correlating findings with disease progression.

Main Results:

• Identified a link between PTX3 deficiency and amplified complement activation, promoting granuloma formation.
• PTX3 deficiency facilitates C5a-mediated mTORC1 activation and macrophage reprogramming towards glycolysis, enhancing proliferation and aggregation.
• This process sustains immune cell recruitment, exacerbates the pro-inflammatory microenvironment, and impacts disease course.

Conclusions:

• PTX3 is a key regulator of complement-mediated signaling in macrophages, restricting granulomatous inflammation in sarcoidosis.
• The PTX3-complement-macrophage axis represents a potential therapeutic target for managing sarcoidosis.
• Understanding PTX3's role provides insights into sarcoidosis pathogenesis and treatment strategies.